Targeted Molecular Imaging
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Wednesday May 11th
Room 511D-F  16:00 - 18:00 Moderators: Peter Caravan and Angelique Lovie

16:00 448.   Theranostic Imaging of Metastatic Prostate Cancer 
Zhihang Chen1, Marie-France Penet1, Sridhar Nimmagadda1, Cong Li1, Sangeeta Ray1, Paul T. Winnard Jr.1, Dmitri Artemov1, Kristine Glunde1, Martin G. Pomper1, and Zaver M. Bhujwalla1
1JHU ICMIC Program, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, United States

Prostate cancer (PCa) is the second leading cause of death from cancer in men in the U.S. The vast majority of men dying of PCa succumb to metastatic androgen-refractory disease. There is therefore a compelling need to find effective treatments for metastatic PCa. In theranostics, noninvasive imaging-based detection of a target is combined with the delivery of a therapeutic payload to the target. Here we are combining prostate-specific membrane antigen (PSMA) based detection of metastatic PCa with a theranostic PSMA-targeted prototype nanoplex carrying multimodality imaging reporters together with small interfering RNA (siRNA) and a prodrug enzyme.

16:12 449.   Positive Contrast for Imaging of Receptor Targeted Magnetic Nanoparticles in the Orthotopic Pancreatic Cancer Xenograft Model Using Ultrashort Echo Time MRI 
Liya Wang1,2, Xiaodong Zhong3, Weiping Qian4, Hongwei Chen1,2, Lily Yang4, and Hui Mao1,2
1Radiology, Emory University School of Medicine, Atlanta, GA, United States, 2Center for Systems Imaging, Emory University, Atlanta, GA, United States, 3MR R&D Collaborations, Siemens Healthcare, Atlanta, GA, United States, 4Surgery, Emory University School of Medicine, Atlanta, GA, United States

The method of ultrashort echo time (UTE) imaging was developed and tested for obtaining positive?contrast from receptor targeted magnetic nanoparticle MRI probes in molecular imaging of pancreatic tumors in animal models. This work demonstrated that UTE imaging may overcome the limitation of negative contrast?or signal reduction from T2 or T2* weighted methods typically used for imaging of magnetic nanoparticle contrast agents.

16:24 450.   MR Imaging guided NCT by a dual Gd/B agent targeted to tumor cells via upregulated LDL transporters. 
Simonetta Geninatti-Crich1, Diego Alberti1, Ibolya Szabo1, Antonio Toppino2, Annamaria Deagostino2, Paolo Venturello2, Nicoletta Protti3, Silva Bortolussi3, Saverio Altieri3, and Silvio Aime1
1University of Torino, Torino, Italy, 2University of Torino, Italy, 3University of Pavia, Italy

MR guided Boron Neutron Capture Therapy (BNCT) has been performed using an imaging probe containing both Boron and Gd, targeted at tumor cells through overexpressed LDLs receptors.

16:36 451.   Multimodal Molecular Imaging of Angiogenesis in a Mouse Model of Melanoma 
Giselle Alexandra Suero Abreu1, Benjamin B Bartelle1, Orlando Aristizábal1, Edward J Houston1, and Daniel H Turnbull1,2
1Skirbal Institute of Biomolecular Medicine, NYU School of Medicine, New York, New York, United States, 2Radiology Department, NYU School of Medicine, New York, NY, United States

Angiogenesis is a critical feature of tumor growth and metastasis, and endothelial cell activation represents one of its main biomarkers. Molecular imaging represents an unique tool for in vivo visualization of the specific abnormalities underlying tumor development. We utilized novel transgenic mice, Ts-Biotag, that genetically biotinylate developing vascular endothelial cells expressing Tie2, and targeted these cells with multiple avidinated probes to achieve contrast enhancement of vessels involved in angiogenesis in a mouse melanoma model. Ts-Biotag mouse melanomas showed selective labeling of neovasculature and has the potential to provide spatiotemporal information about tumor angiogenesis and its relationship to specific disease stages.

16:48 452.   Direct Protein Imaging of Inflammation in the Human Hand 
Jamu K. Alford1, A. Gregory Sorensen1, Thomas Benner1, Blaine A. Chronik2, William Bradfield Handler2, Timothy J Scholl3, Gunjan Madan4, and Peter Caravan1
1Radiology, A. A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, United States, 2Physics and Astronomy, The University of Western Ontario, London, ON, Canada, 3Department of Medical Biophysics, The University of Western Ontario, London, ON, Canada, 4Siemens Medical Solutions Inc., Malvern, PA, United States

The first direct protein imaging in a human volunteer is presented here. Delta relaxation enhanced MR, (dreMR) exploits the strong magnetic field dependence of slowly tumbling (e.g. bound) paramagnetic contrast agent. A volunteer with a broken finger was imaged after injection of the albumin-targeted contrast agent MS-325. A 1.5T, clinical MRI system outfitted with an electromagnetic insert (dreMR insert) was used acquire T1-weighted images at relaxation fields of 1.35 and 1.65T. The difference between the images shows contrast exclusive to the protein-bound contrast agent and demonstrated increased contrast in the inflamed tissue about the finger fracture.

17:00 453.   Molecular MRI of Liver Fibrosis by Fibrin-Fibronectin Targeted Contrast Agent in an Experimental Mouse Model 
April M. Chow1,2, Mingqian Tan3, Darwin S. Gao1,4, Shu Juan Fan1,4, Jerry S. Cheung1,4, Kwan Man5, Zheng-Rong Lu3, and Ed X. Wu1,4
1Laboratory of Biomedical Imaging and Signal Processing, The University of Hong Kong, Pokfulam, Hong Kong SAR, China, People's Republic of, 2Medical Physics & Research Department, Hong Kong Sanatorium & Hospital, Happy Valley, Hong Kong SAR, China, People's Republic of, 3Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, United States, 4Department of Electrical and Electronic Engineering, The University of Hong Kong, Pokfulam, Hong Kong SAR, China, People's Republic of, 5Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong SAR, China, People's Republic of

Liver fibrosis is characterized by an increased amount of fibrin-fibronectin complexes, which may serve as a specific molecular target for contrast-enhanced MRI. In this study, the feasibility of CGLIIQKNEC (CLT1) peptide-targeted nanoglobular contrast agent (Gd-P) for early detection of liver fibrosis through molecular imaging of fibronectin was investigated at 7T in an experimental mouse model of fibrosis. Considerable contrast enhancements were observed and quantified in normal and fibrotic livers using Gd-P and the control non-targeted KAREC peptide nanoglobular contrast agent (Gd-CP) at 0.03mmolGd/kg. Differential enhancements between normal and fibrotic livers were only found for Gd-P. Our results indicate that Gd-P could be used as a fibrin-fibronectin specific MR contrast agent to detect and characterize liver fibrosis at early phase.

17:12 454.   In vivo dynamic contrast enhanced MRI of novel contrast agents targeted to the estrogen receptor 
Adi Pais1, Gunanathan Chidambaram2, Inbal Biton3, Raanan Margalit1, David Milstein2, and Hadassa Degani1
1Biological Regulation, Weizmann Institute of Science, Rehovot, Israel, 2Organic Chemistry, Weizmann Institute of Science, Rehovot, Israel, 3Veterinary Resources, Weizmann Institute of Science, Rehovot, Israel

Molecular imaging of novel contrast agents, targeted to the estrogen receptor (ER), composed of Gd-chelate conjugated to estrogen (EPTA-Gd) or tamoxifen (TPTA-Gd), were investigated in vivo. DCE-MRI, applied in mice bearing human breast cancer tumors showed that EPTA-Gd induced a significantly higher enhancement in MDA-ER-positive tumors than in MDA-ER-negative tumors and muscle tissues, indicating specific binding to ER and heterogeneous ER spatial distribution. In contrast, TPTA-Gd showed high enhancement in muscle tissue and lower and similar enhancement in MDA-ER-positive and negative tumors revealing an unknown interaction with muscle components. In conclusion, EPTA-Gd is a potential molecular imaging probe of ER

17:24 455.   MRI with magnetic nanoparticles serves as a biomarker for the inflammation associated with the early, insulitic phase of Type I Diabetes 
Alexander R Guimaraes1,2, Jason L. Gaglia3,4, Mukesh G. Harisinghani2, Christophe Benoist3,4, Diane Mathis3,4, and Ralph Weissleder1
1Center for Systems Biology, Boston, MA, United States, 2Radiology/Massachusetts General Hospital, Division of Abdominal Imaging and Interventional Radiology, Boston, MA, United States, 3Pathology, Harvard Medical School, Boston, MA, United States, 4Section on Immunology and Immunogenetics, Joslin Diabetes Center, Boston, MA, United States

The early, insulitic phase of type 1 Diabetes (T1D) is accompanied with leaky microvasculature and a macrophage infiltrate. We have developed and validated a technique based on MRI and magnetic nanoparticles (MNP) to allow indirect quantification and visualization of insulitis in animal models of DM. Our translation and application of this technique to a clinical trial involving 22 subjects reveal that changes in T2 may be a surrogate marker of the leaky vasculature and infiltrate associated with, and that this technique may distinguish and monitor patients in the early, insulitic phase of T1D.

17:36 456.   MRI of cells and mice at 1 and 7 Tesla with Gd-targeting agents: when the low field is better! 
Simonetta Geninatti-Crich1, Diego Alberti1, Ibolya Szabo1, Dario Longo1, and Silvio Aime1
1University of Torino, Torino, Italy

A comparison between the efficiency of slowly moving macromolecular MRI imaging probes at 1 and 7 Tesla was carried out using Gd-loaded/LDL (Low Density Lipoproteins) adducts consisting of 250 Gd amphiphilic complexes incorporated in the lipophilic LDL particles. The sensitivity enhancement obtained at 1 Tesla of B16 melanoma cells labeled with Gd-AAZTAC17/LDL adduct is several times higher than that attained at higher fields.

17:48 457.   Enhanced relaxivity of hydroxyapatite-targeted gadolinium contrast agents  -permission withheld
Jonathan Marmurek1,2, Khaled Nasr3, Elena Vinogradov2, Ananth J. Madhuranthakam4, John V. Frangioni3, and Robert E. Lenkinski2
1Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, United States, 2Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States, 3Hematology and Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States, 4Global Applied Science Laboratory, GE Healthcare, Boston, MA, United States

We present a high-relaxivity gadolinium-bisphosphonate contrast agent that specifically targets hydroxyapatite, the malignant form of breast cancer microcalcification. The effect of increasing contrast agent concentration on longitudinal relaxation times measured by ultra-short echo time imaging was consistent with a Langmuir adsorption isotherm. High-affinity binding of the bisphosphonate ligand to hydroxyapatite restricts the rotational freedom of the adsorbed contrast agent and results in an apparent relaxivity exceeding 1000 s-1/mM. This enhancement enables the detection of bound contrast agent at concentrations as low as 1 μM.